Real‐world treatment patterns and clinical outcomes in patients with stage III NSCLC in Korea: The KINDLE study

Abstract Objective KINDLE‐Korea is part of a real‐world KINDLE study that aimed to characterize the treatment patterns and clinical outcomes of patients with stage III non‐small cell lung cancer (NSCLC). Materials and Methods The KINDLE was an international real‐world study that explores patient and disease characteristics, treatment patterns, and survival outcomes. The KINDLE‐Korea included stage III NSCLC patients diagnosed between January 2013 and December 2017. Results A total of 461 patients were enrolled. The median age was 66 years (range: 24–87). Most patients were men (75.7%) with a history of smoking (74.0%), stage IIIA NSCLC (69.2%), and unresectable disease (52.9%). A total of 24.3% had activating EGFR mutation and 62.2% were positive for PDL1 expression. Broadly categorized, 44.6% of the patients received chemoradiation (CRT)‐based therapy, 35.1% underwent surgery, and 20.3% received palliative therapies as initial treatment. The most commonly adopted approaches for patients with stage IIIA and IIIB disease were surgery and CRT, respectively. The median PFS was 15.2 months and OS was 66.7 months. Age >65 years, adenocarcinoma histology, and surgery as the initial treatment were significantly associated with longer OS. Conclusion This study revealed the heterogeneity of treatment patterns and survival outcomes in patients with stage III NSCLC before durvalumab consolidation came into clinical practice. There is an unmet need for patients who are not eligible for surgery as an initial therapy. Novel therapeutic approaches are highly warranted to improve clinical outcomes.

The treatment paradigm has shifted dramatically for stage III, locally advanced, unresectable NSCLC patients with the recent advent of durvalumab consolidation after definitive cCRT, demonstrating a significant benefit in progression-free survival (PFS) and OS. 17 Nonetheless, data on the treatment patterns and clinical outcomes in Korean patients with stage III NSCLC remain limited.
KINDLE was a real-world, multinational study conducted to determine the treatment patterns and clinical outcomes of patients with stage III NSCLC before durvalumab consolidation was introduced into clinical practice. 18Here, we report the results of "KINDLE-Korea," a subgroup analyses on patients from Korea.

| Study design
The KINDLE-Korea study was conducted across eight centers in South Korea as a subset of the global (non-United States and non-European Union), noninterventional KINDLE study. 18The independent ethics committees/institutional review boards of all participating centers approved the study protocol (NCT03725475).This study was conducted under the Helsinki Declaration, International Council for Harmonisation (ICH), Good Clinical Practices (GCP), Good Pharmacoepidemiology Practices (GPP), and relevant noninterventional and/or observational studies legislation.

| Study population
This study included patients aged 18 years or older who were diagnosed with de novo locally advanced stage III NSCLC (according to the AJCC classification system, seventh edition) between January 2013 and December 2017.Patients were excluded if they had an initial diagnosis of stage I or II NSCLC that progressed to stage III disease, had concomitant cancer diagnosed within 5 years of the index date (except for nonmetastatic nonmelanoma skin cancers, or in situ or benign neoplasms), or had a followup duration of <9 months since the initial diagnosis.

| Data collection and study outcomes
Details on data collection and study outcomes have been reported previously. 18PFS was defined as the time from treatment initiation to documented disease progression or death due to any cause, whichever occurred first.OS was defined as the time from initial diagnosis or treatment initiation until death due to any cause.

| Statistical analyses
Descriptive statistics were used to summarize the patient demographics, disease characteristics, and treatment patterns.Categorical variables were presented as percentages, while continuous variables as medians, minimums, and maximums.Median survival estimates (PFS and OS) were determined using the Kaplan-Meier method and compared using the log-rank test.Median survival estimates were reported along with the two-sided 95% confidence interval (CI).Univariate and multivariate models using relevant characteristics associated with PFS and OS were based on Cox proportional hazard regression analyses.All analyses were performed using SAS version 9.4.A p-value ≤0.05 was considered statistically significant.
Overall, 41.9% of the patients had resectable disease.The majority (59.1%) of stage IIIA patients had resectable disease, whereas most patients with stage IIIB disease (90.1%) had unresectable disease (Table S1).
Of the 300 patients whose epidermal growth factor receptor (EGFR) mutational status was available, 24.3% had EGFR-mutant tumor (Table 1).Patients with stage IIIA disease had a higher incidence of EGFR-mutant  S1).In terms of resectability, patients with resectable disease had a higher incidence of EGFR-mutant tumor (33.1%) than those with unresectable disease (18.5%).While EGFR mutations were found more commonly in patients with resectable disease than in those with unresectable disease (33.9 vs. 18.2%) in stage IIIA group, the incidence was similar in stage IIIB group, regardless of resectability (22.2 vs. 18.8%,Table S1).The testing for PD-L1 (programmed cell death ligand 1) expression was more commonly performed in patients with unresectable disease (38.1%) compared to those with resectable disease (26.1%).Overall, 62.2% (92 out of 148 tested) had a positive PD-L1 expression (Table 1).A summary of the antibodies used for PD-L1 testing is shown in Table S2.
For those with stage IIIB disease, CRT (63.6%) was the most commonly adopted treatment, followed by palliative therapy (26.5%) and surgery (9.8%, Figure 1, Table S3).Over the study period, 283 (61.4%) patients experienced recurrent/relapsed disease after the initial treatment, including 101 of 193 (53.7%) patients with resectable disease and 182 of 244 (76.8%) patients with unresectable disease.Among them, 208 (73.5%) received second-line therapy (Table S3).Understandably, most patients were treated with a palliative aim regardless of the initial stage at diagnosis, whereas a minority were treated with CRTbased (18.8% and 14.1% as second-and third-line therapies, respectively) or surgery-based approaches (6.3% and 9.0% as second-and third-line therapies, respectively).Detailed information is provided in Tables S4 and S5.
The median PFS from the time of initial treatment was 15.2 months (95% CI: 13.1-18.0)for the total population; 18.0 (95% CI: 14.7-21.7)and 12.2 (95% CI: 9.7-15.0)months for patients with stages IIIA and IIIB disease, respectively (Figure 2B).As summarized in Table 3, the difference in PFS duration increased according to resectability compared to stages, with median PFS of 26.3 (95% CI: 20.2-40.0)and 11.1 (95% CI: 9.4-13.1)months for those with resectable and unresectable disease, respectively.The initial surgery-based approach demonstrated the longest PFS compared to the other approaches, although it differed significantly according to stage and resectability.In contrast, the CRT-based approach demonstrated a consistent duration of PFS ranging between 10.5 and 12.9 regardless of stages or resectability.
Univariate and multivariate survival analyses were performed using clinically relevant variables and initial treatment modalities (Table 4).In the multivariate analysis, age of more than 65 years, adenocarcinoma histology, and surgery as initial therapy were significantly associated with longer OS (all p < 0.05), while only surgery as initial treatment approach was significantly associated with a longer PFS (hazard ratio: 0.42, 95% CI: 0.28-0.63,p < 0.05).
For the 73 patients diagnosed with EGFR-mutant NSCLC, the primary first-line treatment choice was

| DISCUSSION
This retrospective, real-world study on patients with stage III NSCLC is one of the largest studies of its kind, including 461 Korean patients.Our data provide insights into the treatment approaches and their associated survival outcomes before the era of durvalumab. 19It provides a  reference point for the clinical unmet needs before the introduction of durvalumab consolidation and the associated benefits that can come along with it.
A higher number of patients were first diagnosed through a cancer screening program in the Korean subset (18.9%) than in the global cohort (4.1%). 18This may be attributable to the implementation of the Korean Lung Cancer Screening Project as a nationwide program, which recommended the use of low-dose computed tomography for high-risk patients defined as aged 55-74 years with a smoking history of at least 30 pack-years. 20Furthermore, cancer screening tests are commonly performed as part of employee health checkups.As such, the proportion of patients diagnosed with stage IIIA disease was higher in the Korean subset (69.2%) than in the global KINDLE cohort (55.9%), which could have led to a longer OS of 66.7 months compared to that of 34.9 months for the global KINDLE cohort. 18 found substantial diversity in treatment patterns, with at least 20 different approaches used as initial therapy.Approximately 80% of the patients received curative intent therapy, including surgery-or CRT-based therapies.The most commonly adopted treatment modality was cCRT (34.5%).This is comparable to the results of the global KINDLE data, which reported that cCRT was the most common treatment modality (29.4%). 18Of note, the proportion of patients treated with surgerybased therapy was higher in the Korean subset (31.5%) than in the global KINDLE cohort (21.4%). 18This might be due to the higher number of patients diagnosed with stage IIIA NSCLC in the Korean subset than in the global cohort.
Patient survival outcomes were affected by resectability and initial treatment modality.The number of patients with resectable disease treated with CRT-based or palliative therapies implies that other factors, such as the patient's underlying comorbidities or preference, commonly affect the choice of the initial treatment modality.Multivariate analyses demonstrated that OS was significantly longer in patients who were initially treated with surgery than in those who were not.Consistent with our findings, a realworld study in the Korean population also reported that patients in the surgical group had better survival rates than those in the nonsurgical group. 21The relatively poor survival outcomes of CRT-based (with lack of effective consolidation treatment) or palliative therapies compared to surgery-based therapy warrant a novel strategy of nonsurgical approaches to achieve better disease control.
The decision on the initial treatment of patients with stage III NSCLC became evermore complex since the establishment of post-CRT durvalumab maintenance therapy as the standard practice.This mandated MDT discussions, which were officially introduced in Korea and encouraged by the National Health Insurance Service in August 2014, to optimize patient survival outcomes. 22One fourth (23.4%) of the cases were discussed at the MDT meeting, including 29.3% of the patients with stage IIIA disease and 17.0% of the patients with stage IIIB disease.The number of patients undergoing MDT-led decision-making is increasing and selecting an optimal treatment strategy is expected to improve patient outcomes.The incidence of EGFR-mutant NSCLC is more prevalent in the Asia-Pacific region (36.8%-51.4%),including Korea, than in the Western regions (7%-22%). 14,23,24n our Korean cohort, 24.3% of patients with stage III NSCLC harbored EGFR mutations.Although cCRT followed by durvalumab maintenance is recommended, regardless of EGFR mutation status, for patients with stage III NSCLC, a recent exploratory post hoc subgroup analysis in a limited sample of 35 patients with EGFR mutations from the PACIFIC trial demonstrated similar PFS and OS between patients treated with durvalumab and placebo. 25In another retrospective analysis of 37 patients with unresectable stage III EGFR-mutated NSCLC, PFS was not significantly different between patients who received durvalumab and those who received CRT alone (10.3 months vs. 6.9 months). 26In advanced NSCLC, a lack of efficacy of immune checkpoint inhibitors in patients with EGFR-mutant NSCLC has been demonstrated in both tyrosine kinase inhibitor (TKI)naïve and -resistant settings. 27,28Prospective data on the use of EGFR TKIs for patients with EGFR-mutant stage III unresectable NSCLC are not yet available.The use of EGFR TKIs may be considered as palliative therapy in patients who have unresectable disease or are clinically unfit for surgery, if not administered as part of existing curative-intent treatment regimens.Hence, it is critically important to address whether the identification of EGFR alteration(s) and subsequent treatment with EGFR-TKIs as part of curative-intent treatment strategies affect the treatment outcome in patients with locally advanced NSCLC.The ongoing LAURA trial (NCT03521154) is evaluating the efficacy of a third-generation EGFR-TKI, osimertinib, as maintenance treatment for patients with unresectable, EGFR-mutant, stage III NSCLC who have not progressed following CRT treatment. 29Another ongoing trial (NCT04951635) is evaluating almonertinib, a third-generation EGFR-TKI, after CRT in patients with stage III unresectable NSCLC. 30Results are awaited for both trials.
An inherent limitation of our study lies in its retrospective nature.The results of the subgroup analyses should be interpreted with caution because of the small sample size.Further, the definition of resectability could not be specified because the decisions were made on the basis of individual patient by different physicians and institutions over an extended time period.Nonetheless, data from our KINDLE-Korea cohort could serve as a reference to evaluate treatment outcomes in patients with stage III NSCLC after the establishment of durvalumab maintenance as a standard practice of care.The transition in the treatment paradigm for stage III NSCLC may be even more complex with the high incidence of EGFR-mutant NSCLC in Korea.

ETHICS STATEMENT
This study was conducted under the Helsinki Declaration, International Council for Harmonisation (ICH), Good Clinical Practices (GCP), Good Pharmacoepidemiology Practices (GPP), and relevant noninterventional and/or observational studies legislation.This study was approved by the Institutional Review Board of each participating institution with a waiver for informed consent.
therapy (49.3%), followed by palliative therapy (29.0%) and CRT-based therapy at (21.7%).In terms of PFS, surgery exhibited the longest median PFS of 43.2 months (95% CI: 21.72-60.75).Notably, palliative therapy demonstrated a prolonged median PFS of 20.1 months (95% CI: 11.99-23.72)compared to CRTbased therapy, which had a median PFS of 6.2 months (95% CI: 3.29-15.24).While the sample sizes in these subsets are limited to reach definitive conclusions, it is noteworthy that the observed PFS trends did not align with OS outcomes.Surgery and palliative therapy demonstrated a median OS of 66.7 (95% CI: NC-NC) and 65.4 (95% CI 65.38-NC) months, respectively, whereas the median OS for CRT-based therapy was not reached (TablesS6-S8).

F I G U R E 1
Treatment patterns for Korean patients with stage III NSCLC before the immunotherapy era.cCRT, concurrent chemoradiotherapy; CRT, chemoradiotherapy; CT, chemotherapy; NSCLC, non-small cell lung cancer; RT, radiotherapy; sCRT, sequential chemoradiotherapy.F I G U R E 2 Kaplan-Meier survival curves for (A) overall and (B) progression-free survival according to stage.

T A B L E 1 Baseline characteristics. Parameters, n (%) Number of patients (N = 461)
Current smoker was defined as an active smoker; ex-smoker was defined as having smoked regularly but stopped ≥365 days ago; and never smoker was defined as never smoked regularly.PD-L1 expression was tested using the Dako 22C3, Ventana SP263, or Ventana SP142 assays.
a b Stage according to AJCC Seventh edition.c Overall survival according to stage, resectability, and initial treatment approach.
T A B L E 2 Univariate and multivariate analyses for overall and progression-free survivals.
T A B L E 4Abbreviations: CI, confidence interval; CRT, chemoradiotherapy; and HR, hazard ratio.